7-(d-(alpha-amino-alpha-phenyl-,2-thienyl-and 3-thienyl-acetamido))-3-(1,2,3-thiadiazol-4-or 5-yl)-carbonylthiomethyl-3-cephem-4-carboxylic acids

ABSTRACT

7-(D-(A-AMINO-A-PHENYL-, 2-THIENYL- AND 3-THIENYL-ACETAMIDO)-3-(1,2,3-THIADIAZOL-4-OR 5-YL) CARBONYLTHIOMETHYL3-CEPHEM-4-CARBOXYLIC ACIDS AND THEIR NONTOXIC, PHARMACEUTICALLY ACCEPTABLE SALTS ARE VALUABLE AS ANTIBACTERIAL AGENTS, AS NUTRITIONAL SUPPLEMENTS IN ANIMAL FEEDS, AS AGENTS FOR THE TREATMENT OF MASTITIS IN CATTLE AND AS THERAPEUTIC AGENTS IN POULTRY AND ANIMALS, INCLUDING MAN, AND ARE ESPECIALLY USEFUL IN THE TREATMENT, PARTICULARLY BY ORAL ADMINISTRATION, OF INFECTIOUS DISEASES CUASED BY MANY GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA. ALSO INCLUDED IN THIS INVENTIN ARE THE CORRESPONDING PIVALOYLOXYMETHYL, ACETOXYMETHYL, METHOXYMETHYL, ACETONYL, AND PHENACYL ESTERS OF SUCH ACIDS AND THEIR NONTOXIC, PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS.

United States Patent 3,776,907 7-[D-(oz-A1VHNO-a-PHENYL, Z-TIMNYL- AND 3- THlENYL-ACETANIIDOH 3 (1,2,3-IHIADI- AZOL-4- OR 5-YL)-CARBONYLTHIOMETHYL- 3-CEPHEM-4-CARBOXYLIC ACIDS 5 John Michael Essery and Lee Cannon Cheney, Fayetteville, N.Y., assignors to Bristol-Myers Company, New York, N.Y. No Drawing. Filed June 12, 1972, Ser. No. 261,767 Int. Cl. C07d 99/24 U.S. Cl. 260-243 C 88 Claims 'BACKGROU ND OF THE INVENTION (1) Field of the invention The cephalosporins of the present invention possess the usual attributes of such compounds and are particularly useful in the treatment of bacterial infections by oral administration.

(2) Description of the prior art (A) Cephalosporins in general.Cephalothin and cephaloridine are well-known antibacterial agents; see U.S. Pats. 3,218,318; 3,449,338 and 3,498,979. The literature also contains-considerable data on the activity of cephaloglycin and cephalexin; see U.S. Pats. 3,303,193, 3,507,861 and 3,560,489 and Great Britain 985,747 and 1,054,806. Newer cephalosporins include cefazolin and cephapirin;

see U.S. Pat. 3,516,997 [and also Netherlands 6805179 (Farmdoc 34,328) and South Africa 68/4,513] and U.S. Pat. 3,422,100.

The literature on cephalosporins has been reviewed by E. P. Abraham, Quart. Rev. (London),21, 231 1967) by E. Van Heyningen, Advan. Drug Res., 4, 1-70 (1967) and briefly in Annual Reports in Medicinal Chemistry, Academic Press, Inc., 111 5th Ave., New York, NY. 10003, by L. C. Cheney on pp. 96 and 97 (1967) and by K. Gerzon and R. B. Morin on pp. 90-93 (1968) and by Gerzon on pp. 79-80 (1969) and by L. H. Conover on pp. 101-102 (1970). New cephalosporins are frequently reported at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy as illustrated by Sassiver et al., Antimicrobial Agents and Chemotherapy- 1968, American Society for Microbiology, Bethesda, Md., pp. 101-114 (1969) and by Nishida et al., ibid, 236-243 (1970). Two excellentvreviews are The Cephalosporins; Microbiological, Chemical and Pharmacological Properties and Use in Chemotherapy of Infection, L. Weinstein and K. Kaplan, Annals of Internal Medicine, 72, 729-739 (1970) and Structure Activity Relationships Among Semisynthetic Cephalosporins, M. L. Sassiver and A. Lewis,

Advances in Applied Microbiology, edited by D. Perlman,

ice

13, 163-236 (1970), Academic Press, New York. Two more recent reviews are fl-Lactam Antibiotics: Their Physicochemical Properties and Biological Activities in Relation to Structure, J. P. Hou and I. W. Poole, J. Pharmaceutical Sciences, 60(4), 503-532 (April 1971) and Chemistry of Cephalosporin Antibiotics, R. B. Morin and B. G. Jackson, Fortschr. Chem. Org. Naturst., 28, 343- 403 (1970) which includes a section on nucleophilic displacement of the acetate group at pp. 370-3 73.

The preparation of various 7-[a-amino-arylacetamido] cephalosporanic acids and the corresponding desacetoxy compounds in which aryl represents unsubstituted or substituted phenyl or 2- or 3-thienyl is described, for example, in British specifications 985,747, 1,017,624, 1,054,806 and 1,123,333, in Belgium Pat. 696,026 (Farmdoc No. 29,- 494), in U.S. Pats. 3,311,621, 3,352,858, 3,489,750, 3,489,751, 3,489,752, 3,518,260 and 3,575,969, in Japanese Pat. 16,871/66 (Farmdoc 23,231), by Spencer et al., J. Med. Chem., 9(5), 746-750 (1966), -by Ryan et al., J. Med. Chem., 12, 310-313 (1969) and by Kurita et al., I. Antibiotics (Tokyo) (A), 19, 243-249 (1966) and see also U.S. Pat. 3,485,819. British specification 1,073,530 includes a disclosure of the preparation of such compounds by acylation of sililyated 7-ACA.

Netherlands Pats. 6811676 (Farmdoc 36,349) and 6812382 (Farmdoc 36,496) and U.S. Pats. 3,489,750 and 3,489,751 disclose ring-substituted cephaloglycins.

(B) 3 thiomethylcephalosporins.-Various cephalosporins, including cephalosporin C on occasion but not cephaloglycin, have been reacted with nucleophilic, aromatic mercaptans to produce compounds having the structure In U.S. Pat. 3,278,531 Ar is phenyl or certain substituted phenyls or certain aromatic heterocyclic rings named, for example, in col. 5. Similar nucleophiles, e.g. Z-mercaptopyrimidines, are disclosed in U.S. 3,261,832 and Great Britain 1,101,422 and U.S. 3,479,350 and U.S. 3,502,665, all issued to Glaxo. A parallel disclosure is found in Great Britain 1,109,525 to Ciba, e.g. in definition h for R Additional nucleophiles of this type were disclosed by Fujisawa in Belgium 714,518 (Farmdoc 35,307; Netherlands 6806129 and South Africa 68/2,695), in Canada 818,- 501 (Farmdoc 38,845), in Great Britain 1,187,323 (Farmdoc 31,936; Netherlands 6714888), in U.S. 3,530,123 and in U.S. 3,516,997 (Farmdoc 34,328; Netherlands 6805179) which includes the compound named cefazolin, which has a tetrazolylacetyl sidechain on the 7-amino group and a S-methyl-thiadiazolylthiomethyl group at the 3-position and is described at some length in the scientific literature, e.g. in Antimicrobial Agents and Chemotherapy-1969, American Society for Microbiology, Bethesda, Md., at pp. 236-243 and in J. Antibiotics (Japan), 23 (3), 131- 148 (1970).

, Replacement of the 3-acetoxy group of a cephalosporin by various heterocyclic thiols has been disclosed in U.S. 3,563,983 and in Netherlands 7005519 (Farmdoc 80,- 188R) where the sidechains were, for example, 7-u-aminophenylacetamido and typical heterocyclic thiols Were 2-methyl-1,3,4-thiadiazole 5 thiol and 1-methyl-1,2,3,4- tetrazole-S-thiol. i

Various cephalosporins having the structure where X includes are disclosed in many patents including some of the above and in US. 3,239,516, 3,239,515, 3,243,435, 3,258,461, 3,431,259, 3,446,803, 3,278,531, 3,261,832 and 3,573,298.

Related publications in the scientific literature include J. Med. Chem., 8, 174-181 (1965) and J. Chem. Soc. (London), 1595-1605 (1965), 5015-5031 (1965) and 1959-1963 (1967).

(C) 3-acylthiomethylcephalosporins. The following publications and patents disclose certain additional 7-ACA derivatives containing a 3-acrylthiomethyl moiety (in which phenyl is abbreviated as Ph):

(1) G. F. H. Green, J. E. Page, and S. E. Staniforth, J. Chem. Soc., 1595-605 (1965). This reference gives the proton magnetic resonance spectra of the 3-benzylthiomethyl derivative of cephalothin.

Cocker et al., J. Chem. Soc., 1142-1151 (1966) adds thiopicolinyl and references Belgium 650,444.

(2) J. D. Cocker et al., J. Chem. Soc., 5015-31 (1965) discloses compounds having the structure curs-3G H wherein R has the following meanings:

S RCONH- wherein Y has, for example, the following meanings:

4 where R is CH O-, NO --CN, CH S,

Equivalents are Netherlands 6408066 (Farmdoc 15534) and Great Britain 1,101,424.

(4) Glaxos Netherlands 6506818 (Farmdoc 19,306) discloses the reaction OOH OOH

An equivalent is US. 3,502,665.

(5) Glaxos Netherlands 6411521 [Chem. Abstr., 63:13281d (1965)] discloses the reaction wherein Equivalents are Great Britain 1,101,422 and Canada 796,747 (Farmdoc 17,362).

(6) Cibas US. 3,555,017 discloses compounds having the structure R as in 6 above. Equivalents are Belgium 708,311 (Farmdoc 33,277) and US. 3,557,104.

(8) Cibas Belgium '751,5-26'(Fa'i'mdoc 90,178R) discloses compoundsjghaving the'structuIeTT I... I N CH OO-NH OOH R as in '6 above. An equivalent in Netherlands 70008237. (9) Cibas South Africa 69/ 8,436 discloses compounds having the structure 11 /N s N TNH-O-C 0-NH OOH R as in 6 above. Equivalents are Belgium 743,014 (Farmdoc 43,126R) and Netherlands 69-18611.

10) Cibas South Africa 69/ 8,399 discloses compounds having the structure s N-O-OO-NH OOH R as in 6 above. Equivalents are Belgium 742,933 (Farmdoc 41,568R) and Netherlands 6918531.

(11) Cibas South Africa 68,8,185 discloses compounds having the structure OOH H: N N-O-CO-NH- E O=---N C-S R OOH R as in 6 above. An equivalent in Netherlands 6818868 German 1,817,121 and Belgium 726,316.

(13) Fujisawas Great Britain 1,187,323, for example, at p. 5, lines '67-71 discloses compounds having the strucin which R represents methyl, thienyl, pyridyl, etc. and wherein general disclosure is made of other heterocyclic groups as at pages 1 and 2.

Equivalents are Netherlands 6714888 (Farmdoc 31,936) and U.S. 3,530,123.

. 6 ('14 Fujisawas-Belgium 714,518 (Farmdo'c 35,307) discloses (among many others) compounds having the structure 0 OOH wherein R is defined, e.g. in cols. 1 and 4, to include various heterocyclic groups.

(16) Cibas South Africa 65/6,950 (Farmdoc 22,192) discloses compounds having the structure O O=-N Sti l-R OOH in which R in Example 20 is phenyl. Equivalents are Great Britain 1,109,525 and Canada 807,651.

(17) Glaxos U.S. 3,479,350 discloses a process for producing 3-pyridiniummethyl cephalosporins which utilizes as an intermediate compounds of the type described in references (2) and (3) above.

SUMMARY OF THE INVENTION This invention comprises the compounds of the formula 0 s Ar-oH- LNn-on-or r oH, o NH: 0= N (Loni-SJ: l

C y JJOOR (I) wherein Ar is phenyl, 2-thienyl or 3-thienyl and having the D configuration in the 7-sidechain and existing primarily as the zwitterion when R is hydrogen; wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacyl; and their nontoxic, pharmaceutically acceptable salts.

Such salts include the nontoxic, carboxylic acid salts thereof when R is hydrogen, including nontoxic metallic salts such as sodium, potassium, calcium and aluminum, the ammonium salt and substituted ammonium salts, e.g. salts of such nontoxic amines as trialkylamines, including triethylamine, procaine, dibenzylamine, N-benzyl-betaphenethylamine, l-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine, N,N-bis-dehydroabietylethylenediamine, N-(lower)-alkylpiperidine, e.g., N-ethylpiperidine, and other amines which have been used to form salts with benzylpenicillin; and in all cases the nontoxic acid addition salts thereof (i.e., the amine salts) including the mineral acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate and phosphate and the organic acid addition salts such as the maleate, acetate, citrate, oxalate, succinate, benzoate, tartrate, fumarate, malate, mandelate, ascorbate and the like. I

The compounds of the present invention are prepared according to the present invention by coupling with 7-amino-3-(1,2,3 thiadiazol-4- or 5-yl)carbonyl thiomethyl 3 cephem-4-carboxylic acid (II) (or a salt or easily hydrolyzed ester thereof including those of U.S. Pat. 3,284,451 and U.K. 1,229,453 and any of the silyl esters described in U.S. Pat. 3,249,622 for use with 7-aminopenicillanic acid and used in Great Britain 1,073,- 530) a particular acid or its functional equivalent as an acylating agent for a primary amino group. After coupling, the blocking group is removed to give the desired product. Said acid has the formula Ar-CH-CO OH NHB wherein Ar represents phenyl, Z-thienyl or 3-thieny1 and wherein B represents a blocking group of the type used either in peptide syntheses or in any of the numerous syntheses of a-aminobenzylpenicillin from 2-phenylglycine. Particularly valuable blocking groups are a proton, as in the compound of the formula NHa-HGI or a fi-diketone as in Great Britain 1,123,333, e.g., methyl acetoacetate, in which case the acid containing the blocked amino group is preferably converted to a mixed anh'ydride, as with ethyl chloroformate, before reaction with Compound H or a salt thereof to form the desired product I after acid cleavage.

Further to the discussion above of blocking groups used on the free amino group of the sidechain acid during its coupling with compound H, the blocking group is then removed to form the products of the present invention, e.g., the t-butoxy-carbonyl group is removed by treatment with formic acid, the carbobenzyloxy group is removed by catalytic hydrogenation, the 2-hydroxy-1- naphthcarbonyl group is removed by acid hydrolysis and the trichloroethoxycarbonyl group by treatment with zinc dust in glacial acetic acid. Obviously other functionally equivalent blocking groups for an amino group can be used and such groups are considered within the scope of this invention.

Thus, with respect to said acid to be used to couple with compound II, functional equivalents include the corresponding acid anhydrides, including mixed anhydrides and particularly the mixed anhydrides prepared from stronger acids such as the lower aliphatic monoesters of carbonic acid, or alkyl and aryl sulfonic acids and of more hindered acids such as diphenylacetic acid. In addition, an acid azide or an active ester or thioester (e.g., with p-nitrophenol, 2,4-dinitrophenol, thiophenol, thioacetic acid) may be used or the free acid itself may be coupled with compound H after first reacting said free acid with N,N'-dimethylchloroformiminium chloride [cf. Great Britain 1,008,170 and Novak and Weichet, Experientia XXI, 6, 360 1965)] or by the use of enzymes or of an N,N'-carbonyldiimidazole or an N,N-carbonylditriazole [cf. South African patent specification 63/ 2,684] or a carbodiimide reagent [especially N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide or N-cyclohexyl-N'-(2 morpholinoethyl)carbodiimide; cf. Sheehan and Hess, J. Amer. Chem. Soc., 77, 1067 (1955)], or of alkylylamine reagent [cf. R. Buijle and H. G. Viehe, Angew. Chem. International, edition 3, 582 (1964)], or of a ketenimine reagent [cf. C. L. Stevens and M. E. Mond, J. Amer. Chem. Soc., 80 (4065 or of an isoxazolium salt reagent [cf. R. B. Woodward, R. A. Olofson and H. Mayer, J. Amer. Chem. Soc., 83, 1010 (1961)]. Another equivalent of the acid chloride is a corresponding azolide, i.e., an amide of the corresponding acid whose amide nitrogen is a member of a quasiaromatic fivemembered ring containing at least two nitrogen atoms, i.e., imidazole, pyrazole, the triazoles, benzimidazole, benzotriazole and their substituted derivatives. As an example of the general method for the preparation of an azolide, N,N-carbonyldiimidazole is reacted with a carboxylic acid in equimolar proportions at room temperatures in tetrahydrofuran, chloroform, dimethylformamide or a similar inert solvent to form the carboxylic acid imidazolide in practically quantitative yield with liberation of carbon dioxide and one mole of imidazole. Dicarboxylic acids yield diimidazolide. The by-product, imidazole, precipitates and may be separated and the imidazolide isolated, but this is not essential. The methods for carrying out these reactions to produce a cephalosporin and the methods used to isolate the cephalosporin so produced are well known in the art.

In the treatment of bacterial infections in man, the compounds of this invention are administered orally or parenterally, in accordance with conventional procedures for antibiotic administration, in an amount of from about 5 to 200 mg./kg./day and preferably about 5 to 20 mg./ kg./day in divided dosage, e.g., three to four times a day. They are administered in dosage units containing, for example, or 250 or 500 mg. of active ingredient with suitable physiologically acceptable carriers or excipients. The dosage units are in the form of liquid preparations such as solutions or suspensions or as solids in tablets or capsules.

The preferred esters of the cephalosporins of the present invention are the pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters. All are useful intermediates in the production of the cephalosporin having a free carboxyl group and the first three are also of interest because on oral administration they provide difi'erent rates and amounts of absorption and give differing concentrations of the active antibacterial agent in blood and tissues.

As indicated above, these five esters of 7-aminocephalosporanic acid are each prepared by known methods. One excellent procedure is that of U.S. Pat. No. 3,284,451 in which sodium cephalothin is esterified by reaction with the corresponding active chloro or bromo compound (e.g. phenacyl bromide, chloroacetone, chloromethyl ether, pivaloyloxymethyl chloride [also called chloromethyl pivalate], acetoxymethyl chloride) and then the thienylacetic acid sidechain is removed enzymatically as in the same patent or chemically as in U.S. Pat. No. 3,575,970 and in Journal of Antibiotics, XXIV (11), 767-773 1971 In another good method the triethylamine salt of 7-aminocephalosporanic acid is reacted directly with the active halogen compound, as in UK. 1,229,453.

These esters of 7-aminocephalosporanic acid are then reacted with the nucleophile in the same manner as is illustrated herein for 7-aminocephalosporanic acid itself. The 3-thiolated ester of 7-aminocephalosporanic acid is then coupled with the 2-arylglycine, e.g. D-()-2-phenylglycine, as before. Before or after removal of any blocking group on the a-amino group of the 2-arylglycine sidechain, the ester of the cephalosporin so obtained is, if not used per se, converted to its free acid, including its zwitterion (and, if desired, any salt) by removal of the esterifying group, as by aqueous or enzymatic hydrolysis (as with human or animal serum) or acidic or alkaline hydrolysis or by treatment with sodium thiophenoxide as taught in U.S. 3,284,451 and, in the penicillin series, by Sheehan et al., J. Org. Chem., 29(7), 20062008 (1964).

In another alternative synthesis, the 3-thiolated 7-aminocephalosporanic acid is prepared as described herein and then acylated at the 7-amino group and finally esterified, as by reaction of the appropriate alcohol with the acid chloride prepared, for example, by reaction of the final cephalosporin with thionyl chloride or by other essentially acidic esterification procedures.

The preferred and most active compounds of the present invention are those having the D configuration at the acarbon atom in the 7-sidechain, that is, those made from D-(-)-2-phenylglycine, which is also called D-(-)-mby. fermentation and in the -7-aminocephalosporanicacid derived therefrom.

1,2,3-thiadiazole--thiocarboxylic acid, potassium salt, III, 1,2,S-thiadiazole-S-carboxylic acid, I

This acid was described by D. L. Pain and R. Slack, J. Chem. Soc., 5166 (1965) and by R. Raap and Micetich, Can. J. Chem., 46, 1057 (1968).

1,2,3-thiadiazole-5-carbonyl chloride, II

II was prepared by suspending in dry, boiling benzene (50 ml.) containing about five drops of dimethylformamide the acid I (15.4 g., 118 mmoles) and adding dropwise (under a N atmosphere) oxalyl chloride (18.9 g., 147 mmoles). After a two hour reflux period the mixture was cooled, concentrated and distilled to give the acid chloride II.

1,2,3-thiadiazole-5-thiocarboxylic acid, potassium salt, III

The above acid chloride H, 15.6 g., 105 mmoles, dissolved in dry benzene (40 ml.) was added dropwise under N to a solution of freshly prepared KSH, from 210 mmoles K in 200 ml. of dry ethanol saturated with H 8 and stirred and maintained at 5 C. After stirring at 5 C. for two hours the mixture was concentrated in vacuo at 30-35 C. to leave a yellow solid containing ca. 67% of III, 27.2 g.

1,2,3-thiadiazole-4-thiocarboxylic acid, potassium salt 1,2,3-thiadiazole-4-carbonyl chloride, IV

This acid chloride was described by D. L. Pain and R. Slack, J. Chem. Soc., 5166 (1965).

1,2,3-thiadiazole-4-thiocarboxylic acid, potassium salt, V

This "compound was prepared, as described above for III, from the acid chloride IV (24.6 g., 165 mmoles) and KSH (from 330 mmoles of K, 300 ml. of ethanol and H S): yellow solid, 41.2 g. NMR analysis 67% of V.

7 -amino-3-( 1,2,3 -thiadi azol-4-y1) carbonylthiomethyl- 3-cephem-4-carb oxylic acid To a slury of 27.2 g. (.1 mole) of 7-aminocepha1osporanic acid.,and.8.4 g. (.1, mole) of sodium bicarbonate in 600 m1. of 0.1 M aqueous phosphate (buffered at pH 6.4) was added with stirring 27.4 g. (.1 mole) of potassium '1,2,3-thiadiazole-4-thiocarboxylate (estimated purity 67% by weight, contaminant potassium chloride). The mixture was heated under a nitrogen atmosphere for five hours at 50, and was then allowed to cool to room temperature. The product which precipitated was collected by filtration, washed with water and acetone and dried in vacuo over phosphorus pentoxide to give 22.8 g., 64%. The infrared and NMR spectra of this product were consistent with the structure.

Analysis.-Calcd. for C H N O S (percent): C, 36.86; H, 2.81; N, 15.63. Found (percent): C, 36.95; H, 3.06; N, 15.00.

Pivaloyloxymethyl 7-amino-3-(1,2,3-thiadiazol-4-yl) carbonylthiomethyl-3-cephem-4-carboxylate Method A.-The title compound is produced by substituting for the 7-aminocephalosporanic acid used immediately above an equimolar weight of pivaloyloxymethyl 7-aminocephalosporanate hydrochloride prepared according to Example 2 of U.K. 1,229,453 from 7-aminocephalosporanic acid. Germany 1,904,585 (Farmdoc 39,445) is equivalent to UK. 1,229,453.

Method B.'Ihe title compound is produced by substituting for the 0.025 mole (6.8 g.) 7-aminocephalosporanic acid used in the procedure of Example 2 of UK. 1,229,453 an equimolar Weight of 7-amino-3-(1,2,3-

10 thiadiazol 4 y1)carbonylthiomethy1-3-cephem-4-carbox# ylic acid.

The respective acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters of 7-arnino-3-(1,2,3-thiadiazol-4-yl) carbonylthiomethyl-3-cephem-4-carboxylic acid are prepared by substituting in Method B above for the chloromethyl pivalate used therein an equimolar weight of chloromethyl acetate, chloromethyl methyl ether, chloroacetone and phenacyl bromide, respectively.

Acetoxymethyl 7-amino-3-(1,2,3-thiadiazolyl-4-yl) carbonylthiomethyl-3-cephem-4-carboxylate The title compound is produced by substituting for the 7-aminocephalosporanic acid used above (in the reaction with 1,2,3-thiadiazol-4thiocarboxylic acid) an equimolar weight of acetoxymethyl 7-aminocepha1osporanate hydrochloride prepared according to Binderup et al., Journal of Antibiotics, XXIV (11), 767-773 (November 1971).

In a similar fashion the respective pivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters of 7-aminocephalosporanic acid are prepared (as hydrochlorides) by replacing the chloromethyl acetate in the procedure of Binderup et al., ibid., with equimolar Weights of chloromethyl pivalate, chloromethyl methyl ether, chloroacetone and phenacyl bromide, respectively. Each of these hydrochloride esters of 7-ACA is then reacted as was the acetoxymethyl ester hydrochloride to produce the corresponding ester of 7-amino-3-(1,2,3-thiadiazol-4-yD-carbonylthiomethyl-3-cephem-4-carboxy1ic acid.

7-amino-3 (1,2,3-thiadiazol-5-y1)carbonylthiomethyl- 3-cephem-4-carboxylie acid To a suspension of 27.2 g. (.1 mole) of 7-aminocephalosporanic acid in 400 ml. of 0.1 M aqueous phosphate (buttered at pH 6.4) was added 10 ml. of methyl isobutyl ketone followed by 8.4 g. (.1 mole) of sodium bicarbonate. Potassium 1,2,3-thiadiazole-S-thiocarboxylate (27.1 g., estimated purity 67% by weight, contaminant potassium chloride, .0985 mole) was added and the mixture was stirred under a nitrogen atmosphere for 3.5 hr. at 56. The mixture was cooled and filtered to provide a solid which was washed with water and acetone and dried in vacuo over phosphorus pentoxide. Yield 4.1 g., M.P. 200 dec. Infrared and NMR spectra were consistent with structure.

Analysis.Calcd. for C H N O S 0.5H O (percent) C, 35.96; H, 3.02; N, 15.25; Hp, 2.45. Found (percent): C, 37.03; H, 3.13; N, 14.77; H 0, 2.58.

A second crop of 5.0 g. was obtained by adjusting the pH of the filtrate to 5.5 with 6 N hydrochloric acid and collecting the solid as above.

Pivaloyloxymethyl 7-amino-3-(1,2,3-thiadiazol-5-yl) carbonylthiomethyl-3-cephem-4-carboxylate Method A.-'Ihe title compound is produced by substituting for the 7-aminocephalosporanic acid used immediately above an equimolar weight of pivaloyloxymethyl 7-aminocephalosporanate hydrochloride prepared according to Example 2 of UK. 1,229,453 from 7-aminocephalosporanic acid. German 1,904,585 (Farmdoc 39,445) is equivalent to UK. 1,229,453.

Method B.-The title compound is produced by substituting for the 0.025 mole (6.8 g.) 7-aminocephalosporanic acid used in the procedure of Example 2 of UK. 1,229,453 an equimolar weight of 7-amino 3 (1,2,3- thiadiazol 5 yl)carbonylthiomethyl 3-cephem-4-carboxylic acid.

The respective acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters of 7- amino 3 (1,2,3-thiadiazol- 5-y1)carbonylthiomethyl-3-cephem-4-carboxylic acid are prepared by substituting in Method B above for the chloromethyl pivalate used therein an equimolar weight of chloromethyl acetate, chloromethyl methyl ether, chloroacetone and phenacyl bromide, respectively.

1 1 Acetoxymethyl 7-amino-3-(1,2,3-thiadiazol-5-yl) carbonylthiomethyl-3-cephem-4-carboxylate The title compound is produced by substituting for the 7-arninocephalosporanic acid used above (in the reaction with 1,2,3-thiadiazol-S-thiocarboxylic acid) an equimolar weight of acetoxymethyl 7-aminocephalosporanate hydrochloride prepared according to Binderup et al., Journal of Antibiotics, XXIV (11), 767-773 (November 1971).

In a similar fashion the respective pivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters of 7-aminocephalosporanic acid are prepared (as hydrochlorides) by replacing the chloromethyl acetate in the procedure of Binderup et al., ibid., with equimolar weights of chloromethyl pivalate, chloromethyl methyl ether, chloroacetone and phenacyl bromide, respectively. Each of these hydrochloride esters of 7-ACA is then reacted as was the acetoxymethyl ester hydrochloride to produce the corresponding ester of 7 amino 3 (1,2,3-thiadiazol--yl) carbonylthiomethyl-3-cephem-4-carboxylic acid.

The following examples are given in illustration of, but not in limitation of, the present invention. All temperatures are given in degrees centigrade. 7-aminocephalosporanic acid is abbreviated as 7-ACA and methyl isobutyl ketone as MIBK. Skellysolve B is a petroleum ether fraction of B.P. 60-68 C. consisting essentially of n-hexane.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1.-7 [D(-)-a-aminophenylacetamido] 3- 1,2,3 thiadiazol 4 yl)carbonylthiomethyl 3- cephem-4-carboxylic acid To a stirred slurry of 17.9 g. (.05 mole) of 7-amino- 3 (1,2,3-thiadiazol-4yl)carbonylthiomethyl-3-cephem-4- carboxylic acid in 400 ml. of dry methylene chloride were added in succession 9.1 g. (.09 mole) of triethylamine, 13.3 g. (.11 mole) of N,N-dimethylaniline and 16.3 g. (.15 mole) of trimethylchlorosilane. The mixture was heated under reflux for 30 minutes, then cooled to 5 singlet (1H) at 5.28 for the benzylic proton; AB quartet (2H) centered at 4.22 due to the exocyclic methylene protons: AB quartet (2H) centered at 3.57 due to the protons at C of the dihydrothiazine ring.

Analysis.Calcd. for C H N O S -H O (percent): C, 44.78; H, 3.76; N, 13.74; E 0, 3.53. Found (percent): C, 45.84; H, 3.96; N, 13.12; H O, 3.43.

This sample of 7-[D-a-aminophenylacetamido]-3-(1,2,

10 3 thiadiazole 4 yl)carbonylthiomethyl 3 cephem 4- carboxylic acid (called new compound) after solution in nutrient broth Was found to exhibit the following minimum inhibitory concentrations (M.I.C.) in meg/ml. versus the indicated microorganisms as determined by overnight incubation at 37 C. by tube dilution. One old,

orally absorbed cephalosporin was included.

TABLE 1 M.I.C. in meg/m1.

. New Cepha- Orgamzm cpd. lexin D. pneumoniae pins 5% serum A9585 .08 16 Str. pyogenea plus 5% serum 1 A9604 08 .3 S. aureus Smith A9537 .3 .6

S. aureus Smith 1 plus 50% serum A9537 32 2.5 S. aureus BX1633-2 at 10J dil'n A9606 0. 3 2 S. aureaus BX16332 at 10 diln. A9606 1 2 S. aureus moth-resist; at 10- di1n A15097 2 32 S. aureus at 10 dil'n A9748 2 32 4 63 .08 2 1 8 2 16 0. 5 8 1M 2 4 16 Pr. mimbilia B--- 1 8 Pr. momanii 2 16 125 Pr. aeruginosa 125 125 35 ,Senmarcercens A20019 125 5 50% nutrient broth-% antibiotic assay broth. 1 At 10- dilution.

Blood levels in the mouse after oral administration 40 were determined with the following results:

S m-001m NH: N Blood level in mcg./m1.

CHzB 0 Hours after administration I Dose, C O OH mgm./kg. 0.5 1 2 3. 5

O S 100 17. 7 11. 8 3. 8 0. 8 -s-t -H (cephalexim-monohy 100 54.6 39.0 7.9 2. 9

Example 2.Sodium 7-[D-(a-amino-a-phenylacetam- D()-phenylglycyl chloride hydrochloride (11.3 g., 0.55 mole) was added and the mixture was stirred for 40 minutes at 57 and for one hour without external cooling. The mixture was added to 200 ml. of water with stirring and the insoluble material was removed by filtration. The aqueous phase of the filtrate was diluted with ml. of methanol and the pH was adjusted to 4.0 with 2 N sodium hydroxide solution. The white solid which precipitated was collected by filtration, washed with water, acetone and ether and dried in vacuo. The product was slurried for 20 minutes in 150 ml. of dry ether, collected and dried in vacuo to provide 5.8 g., 24%, of white amorphous solid M.P. ISO-182 dec. Infrared spectrum (KBr disc) had absorption maxima (cm.- at 1780 (fi-lactam carbonyl), 1690 (amide carbonyl), 1665 (thiolester carbonyl), 1610 and 1390 (carboxylate), 705 (phenyl). The nmr spectrum of a solution of the product in d -dimethylsulfoxide: deuterium oxide (1:2) and deuterium chloride (trace) showed absorptions [ppm (6) from tetramethylsilane] which were assigned as follows: singlet (1H) at 9.69 due to the thiadiazole ring proton; singlet (5H) at 7.52 for the benzene ring protons; doublets centered at ido)] 3 (1,2,3 thiadiazol 4 yl)carbonylthiomethyl-3-cephem-4-carboxylate Example 3.7 [D a amino a (3 thienyl) acetamido] 3 (1,2,3 thiadiazol 4 yl) carbonylthiomethyl-3-cephem-4-carboxylic acid This compound is prepared by substituting an equimolar weight of D-( x-amino-ot-(3-thienyl)-acetyl chloride hydrochloride in the procedure of Example 1 for the D-('-)-a-amino-a-phenylacetyl chloride hydrochlo ride used therein.

. 13 Example 4.--7 [D a amino a (2 thienyl) acetamido] 3 (1,2,3 thiadiazol 4 yl)carbonylth.iomethyl-3-cephem-4-carboxylic acid Following the exact same procedure as in Example 1 except using an equimolar weight of D-( )-a-amino-a- (2-thienyl)-acetylchloride hydrochloride in place of the D-(-)-2-phenylglycyl chloride hydrochloride used therein gives this compound.

Example 5.-Acetoxymethyl 7-[D-a-aminophenylacetamido] 3 (1,2,3 thiadiazol 4 yl)carbonylthio methyl-3-cephem-4-carboxylate To a solution of acetoxymethyl 7-amino-3-(1,2,3-thiadiazol 4 yl)carbonylthiomethyl 3 cephem 4 carboxylate (regenerated from 0.009 mole of its hydrochloride) in 30 ml. ethyl acetate is added 0.020 mole pyridine. The mixture is cooled in ice and stirred while 0.010 mole D-()-2-phenylglycine chloride hydrochloride in 30 ml. ethyl acetate is added over ten minutes. After a further twenty minutes in the cold, stirring is continued at room temperature for one hour. Then the mixture is washed successively with aqueous sodium bicarbonate, 0.1 N hydrochloric acid and water, dried and evaporated in vacuo to leave the desired acetoxymethyl 7- [D-u-aminophenylacetamido] 3 (1,2,3 thiadiazol 4 yl)carbonylthiomethyl-3-cephem-4-carboxy1ate as an oil which crystallizes on trituration in cyclohexane.

The respective pivaloyloxymethyl, methoxymethyl, acetonyl, and phenacyl esters corresponding to the above acetoxymethyl ester are produced by replacing the acetoxymethyl 7 amino 3 (1,2,3-thiadiazol-4-yl)carbonylthiomethyl-3-cephem-4-carboxylate hydrochloride used in the above procedure with 0.009 mole of the hydrochloride of pivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters of 7-amino-3-(1,2,3-thiadiazol-4-yl)carbonylthiomethyl-3-cephem-4-carboxylic acid, respectively.

Example 6.-7 [D a aminophenylacetamido]- 3 (1,2,3 thiadiazol 5 yl) carbonylthiomethyl 3- cephem-4-carboxylic acid To a stirred suspension of 7.16 g. (.02 mole) of 7- amino 3 (1,2,3 thiadiazol 5 yl)carbonylthiomethyl- 3-cephem-4-carboxylic acid in 100 ml. of dry methylene chloride were added 5.2 ml. (.037 mole) of triethylamine vacuo over phosphorus pentoxide to give 2.65 g. of amorphous solid, M.P. 195 dec. The infrared spectrum (BKr disc) showed absorption maxima (cm." at 1775 (13 lactam carbonyl) 1690 (amide carbonyl), 1640 (thiolester carbonyl), 1610 and 1390 (carboxylate), 700 (phenyl). The NMR spectrum of a solution of the product in d dimethylsulfoxide: deuterium oxide (1:2 containing deuterium chloride (trace) showed absorptions [p.p.rn. [5] from tetramethylsilane] which were assigned as follows: singlet (1H) at 9.30 due to the thiadiazole ring proton; singlet (5H) at 7.51 for the benzene ring protons; doublets centered at 5.72 (1H) and 5.12 (1H) for the B-lactam protons; singlet (1H) at 5.28 due to the benzylic proton; AB quartet (2H) centered at 4.25 for the exocyclic methylene protons; AB quartet (2H) centered at 3.58 due to the protons of at C of the dihydrothiazine ring.

Analysis.-Calcd. for C H N O5S -05H O (percent): C,45.50;H, 3.62; N, 13.96; H O, 1.80. Found (percent): C, 46.97; H, 3.85; N, 13.11; H O, 2.88.

This sample of 7- [D-a-aminophenylacetamido]-3-( 1,2, 3 thiadiazole 5 yl)carbonylthiomethyl 3 cephem- 4-carboxylic acid (called new compound) after solution in nutrient broth was found to exhibit the following minimum inhibitory concentrations (M.I.C.) in meg/ml. versus the indicated microorganisms as determined by overorally absorbed cephalosporin was included.

TAB LE 2 M.I.O. in meg-[ml New Cepha- Organism cpd. lexin D. pneumoniae plus 5% serum A9585 3 16 Str. pyoqems plus 5% serum A9604 .3 3 S. aureus Smith 2 A9537 .6 6 S. aureus Smith 1 plus serum 9537 16 2. 5 S. aureus BX16332 at 10 diln--. A9606 1. 3 2 S. aureus BX1633-2 at 10- diln A9606 4 2 S. aureus moth-resist; at 10- diln. A15097 4 32 S. aureus at 1M diln A9748 8 32 S. aureus at 10- dil A9748 16 63 s A9531 .3 2 A15119 8 8 i A9675 32 16 K. pneumom'ae A9977 4 8 p 1 A15130 32 16 Pr. mirabilisk. A9900 4 8 Pr. morgam'ik. A15153 32 125 Pr. aeruginosa... A9843A 125 125 Ser. wmzrcescems A20019 63 125 1 50% nutrient; broth-45% antibiotic assay broth.

1 At 10- dilution.

Blood levels in the mouse after oral administration were determined with the following results:

NH: Blood level in mcgJml.

CH2R O D Hours after administration ose 0011 m m k f 0.5 1 2 as H (cephalexin)-monohydrate $8 g with 3 ml. of a 33% solution of N,N-dimethylaniline hydrochloride in methylene chloride and 5.0 g. (.024 mole) of D-(-)-phenylglycyl chloride hydrochloride. The reaction mixture was stirred at 10 to 12 for 2.5 hrs. Water ml.) was added followed by 20% sodium hydroxide solution to give pH 2.0. The precipitated solid was collected and dissolved in 200 ml. of 50% aqueous methanol at pH 1.5 (addition of 6 N hydrochloric acid) and stirred for 10 min. with 3 g. of (Darko KB) activated charcoal. The slurry was filtered and the filtrate was treated with 20% sodium hydroxide solution to pH 4.0. The product which precipitated was collected by fil- Example 7.Sodium 7 [D (a-amino-u-phenylacetamido)] 3 (1,2,3-thiadiazol-5-yl)-carbonylthiomethyl-3- cephem-4-carboxylate To a stirred aqueous suspension of the zwitterionic form of 7- [D-(oz-amino-u-phenylacetamido) ]-'3- 1,2,3-thiadiazol-5-yl) carbonylthiomethyl-3-cephem-4-carboxylic acid (0.8 mmole) is added 1 N aqueous sodium hydroxide at room temperature until a clear solution (pH 10.8) is obtained. This solution is immediately freeze-dried to give impure, solid sodium 7- [D-(u-amino-u-phenylacetamido)] 3 (1,2,3-thiadiaZol-5-yl) carbonylthiomethyl-3-cephem-4- tratiou, washed with water and acetone and dried in carboxylate.

Example '8.7 [D-a-amino-u-(3-thienyl)-acetamido]-3- (1,2,3 thiadiazol -yl)carbonylthiomethyl-B-cephem- 4-carboxylic acid This compound is prepared by substituting an equimolar weight of D-(-)-a-amino-a-(3-thienyl)acetyl chloride hydrochloride in the procedure of Example 6 for the D- ()-u-amino-a-phenylacetyl chloride hydrochloride used therein.

Example 9.7 [D-a-amino-a-(2-thienyl)-acetamido]-3- (1,2,3 thiadiazol 5-yl)carbonylthiomethyl-3-cephem- 4-carboxylic acid Following the exact same procedure as in Example 6 except using an equimolar weight of D-()-a-amino-u- (Z-thienyl)-acetylchloride hydrochloride in place of the D()-2-phenylglycyl chloride hydrochloride used therein gives this compound.

Example 10.-Acetoxymethyl 7-[D-ot-aminophenylacetamido] 3 (1,2,3-thiadiazol-5-yl)carbonylthiomethyl- 3-cephem-4-carboxylate To a solution of acetoxymethyl 7-amino-3-(1,2,3-thiadiazol-S-yl)carbonylthiomethyl 3-cephem-4-carboxylate (regenerated from 0.009 mole of its hydrochloride) in 30 ml. ethyl acetate is added 0.020 mole pyridine. The mixture is cooled in ice and stirred while 0.010 mole D-()-2-phenylglycine chloride hydrochloride in 30 ml. ethyl acetate is added over ten minutes. After a further twenty minutes in the cold, stirring is continued at room temperature for one hour. Then the mixture is washed successively with aqueous sodium bicarbonate, 0.1 N hydrochloric acid and water, dried and evaporated in vacuo to leave the desired acetoxymethyl 7-[D-a-aminophenylacetamido] 3 (1,2,3 thiadiazol 5 yl)carbonylthiomethyl-3-cephem-4-carboxylate as an oil which crystalizes on trituration in cyclohexane.

The respective pivaloyloxymethyl, methoxymethyl, acetonyl, and phenacyl esters corresponding to the above acetoxymethyl ester are produced by replacing the acetoxymethyl 7-amino-3-(1,2,3-thiadiazol-S-yl)carbonylthiomethyl-3-cephem-4-carboxylate hydrochloride used in the above procedure with 0.009 mole of the hydrochloride of pivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters of 7-amino-3-(1,2,3-thiadiazol-5-yl)carbonylthiomethyl-3cephem-4-carboxy1ic acid, respectively.

We claim:

1. A compound having the D configuration in the 7- sidechain and the formula wherein Ar is phenyl, 2-thienyl or 3-thienyl; R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacyl; or a nontoxic, pharmaceutically acceptable salt thereof.

2. An acid having the D configuration in the 7-sidechain and the formula C JOOH wherein Ar is phenyl, 2-thienyl or 3-thienyl.

3. The sodium salt of a compound of claim 2. 4. The potassium salt of a compound of claim 2. 5. The zwitterion form of a compound of claim 2.

6. A nontoxic, pharmaceutically acceptable acid addition salt of a compound of claim 2.

7. The pivaloyloxymethyl ester of an acid of claim 2.

8. The acetoxymethyl ester of an acid of claim 2.

9. The methoxymethyl ester of an acid of claim 2.

10. The acetonyl ester of an acid of claim 2.

11. The phenacyl ester of an acid of claim 2.

12. A compound of claim 1 having the D configuration in the 7-sidechain and the formula wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacyl; or a nontoxic, pharmaceutically acceptable salt thereof.

13. The acid of claim 12 having the D configuration in the 7-sidechain and the formula 0 s @CH-iiP-NH-CH-Cfi cH, o S I IH. 0=iJ--1 I iv-om-s-iil C N: coon 14. The sodium salt of the compound of claim 13.

15. The potassium salt of the compound of claim 13.

16. The zwitterion form of the compound of claim 13.

17. A nontoxic, pharmaceutically acceptable acid addition salt of the compound of claim 13.

18. The pivaloyloxymethyl ester of the acid of claim 13.

19. The acetoxymethyl ester of the acid of claim 13.

20. The methoxymethyl ester of the acid of claim 13.

21. The acetonyl ester of the acid of claim 13.

22. The phenacyl ester of the acid of claim 13.

23. A compound of claim 1 having the D configuration in the 7-sidechain and the formula lorr-ii-Nn-on-on on,

wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacyl; or anontoxic, pharmaceutically acceptable salt thereof.

24. The acid of claim 2 having the D configuration in the 7-sidechain and the formula 25. The sodium salt of the compound of claim 24.

26. The potassium salt of the compound of claim 24.

27. The zwitterion form of the compound of claim 24.

28. A nontoxic, pharmaceutically acceptable acid addition salt of the compound of claim 24.

29. The pivaloyloxymethyl ester of the acid of claim 24.

30. The acetoxymethyl ester of the acid of claim 24. 31. The methoxymethyl ester of the acid of claim 24. 32. The acetonyl ester of the acid of claim 24.

33. The phenacyl ester of the acid of claim 24.

1 7 34. A compound of claim 1 having the D configuration in the 7 sidechain and the formula s c N:

coon

wherein R is hydrogen, pivaloyloxymethyl, Iacetoxymethyl, methoxymethyl, acetonyl or phenacyl; or a nontoxic,

pharmaceutically acceptable salt thereof.

35. The acid of claim 2 having the D configuration in the 7-sidechain and the formula 36. The sodium salt of the compound of claim 35.

37. The potassium salt of the compound of claim 35.

38. The zwitterion form of the compound of claim 35.

39. A nontoxic, pharmaceutically acceptable acid addition salt of the compound of claim 35.

40. The pivaloyloxymethyl ester of the acid of claim 35.

41. The acetoxymethyl ester of the acid of claim 35.

42. The methoxymethyl ester of the acid of claim 35.

43. The acetonyl ester of the acid of claim 35.

44. The phenacyl ester of the acid of claim 35.

45. A compound having the D configuration in the 7-sidechain and the formula NH. onn paaawj wherein Ar is phenyl, 2-thienyl or B-thienyl.

47. The sodium salt of a compound of claim 46. 48. The potassium salt of a compound of claim 46. 49. The zwitterion form of a compound of claim 46. 50. A nontoxic, pharmaceutically acceptable acid addition 'salt of a compound of claim 46.

51. The pivaloyloxymethyl ester of an acid of claim 46. 52. The acetoxymethyl ester of an acid of claim 46. 53. The methoxymethyl ester of an acid of claim 46. 54. The acetonyl ester of an acid of claim 46. 55. The phenacyl ester of an acid of claim 46. 56. A compound of claim 45 having the D configuration in the 7-sidechain and the formula 57. The acid of claim 46 having-the D configuration in the 7-sidechain and the formula 58. The sodium salt of the compound of claim 57.

59. The potassium salt of the compound of claim 57.

60. The zwitterion form of the compound of claim 57.

61. A nontoxic, pharmaceutically acceptable acid addition salt of the compound of claim 57.

62. The pivaloyloxymethyl ester of the acid of claim 57.

63. The acetoxymethyl ester of the acid of claim 57.

64. The methoxymethyl ester of the acid of claim 57.

65. The acetonyl ester of the acid of claim 57.

66. The phenacyl ester of the acid of claim 57.

67. A compound of claim 45 having the D configuration in the 7-sidechain and the formula LOOR wherein R is hydrogen, pivaloyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl or phenacyl; or a nontoxic, pharmaceticually acceptable salt thereof.

68. The acid of claim 46 having the D configuration in the 7-sidechain and the formula COOH 69. The sodium salt of the compound of claim 68.

70. The potassium salt of the compound of claim 68.

71. The zwitterion form of the compound of claim 68.

72. A nontoxic, pharmaceutically acceptable acid addition salt of the compound of claim 68.

73. The pivaloyloxymethyl ester of the acid of claim 68.

74. The acetoxymethyl ester of the acid of claim 68.

75. The methoxymethyl ester of the acid of claim 68.

76. The acetonyl ester of the acid of claim 68- 77. The phenacyl ester of the acid of claim 68.

78. A compound of claim 45 having the D configuration in the 7-sidechain and the (formula OOR 80. The sodium salt of the compound of claim 79. 88. The phenacyl ester of the acid of claim 79.

81. The potassium salt of the compound of claim 79.

82. The zwitterion form of the compound of claim 79. References cued 83. A nontoxic, pharmaceutically acceptable acid addi- UNITED STATES PATENTS tion salt of the compound of claim 79.

84. The pivaloyloxymethyl ester of the acid of claim 5 3641O21 2/1972 Ryan 260 239'1 79. NICHOLAS S. RIZZO, Primary Examiner 85. The acetoxymethyl ester of the acid of claim 79.

86. The methoxymethyl ester of the acid of claim 79. US. Cl. X.R.

87. The acetonyl ester of the acid of claim 79. 10 24246 

